There is growing evidence that in many cancers, tumors are initiated maintained by rare populations of dysregulated cells with stem cell-like properties, collectively known as cancer stem cells (“CSCs”). These CSCs possess the hallmark stem cell properties of self-renewal and multipotent differentiation capacity. It is also these same properties of CSCs that promote the pronounced effects of CSCs in cancer disease generation and progression, through initiation of tumor formation, chemoresistance, bulk generation of heterogenous tumor cells, and malignancy. Despite this increasing evidence for the critical role of CSCs in cancer development, the cellular origins of CSCs remains highly obscured and positive identification of mammary CSCs (“maCSCs”) in the specific context of breast cancer remains elusive. The picture is even more difficult to ascertain, given that the mere existence of human mammary stem cells (“maSCs”) is controversial. This lack of understanding creates highly divergent possibilities of maCSCs arising from endogenous stem cells altered through genetic mutation, or from dedifferentiation of adult somatic cells. Which mechanism accounts for breast cancer pathogenesis remains a totally unanswered question.
Clearly, establishing the existence and identifying the biological characteristics of human maSCs and their progeny would also be a helpful first step in advancing identification of mammary CSCs (“maCSCs”) in breast cancer. An improving understanding of breast cancer as subtypes possessing genetic signatures similar to a cell-of-origin, identifying both maSCs and maCSCs would shed light on crucial questions related to mechanisms of stem-cell origin or adult dedifferentiation. Ultimately, identifying the relevant pathological actors and mechanisms of cancer parthenogenesis would allow distinguishing between maSCs, normal mammary gland tissue cells, bulk tumor cells and maCSCs, thereby allowing development of targeted therapeutic approaches for cancer treatment. Present efforts to hone in on maSC or maCSC populations are severely hampered by the fact that primary normal and tumor mammary epithelial cells can only be cultured for short periods of time before they cease proliferating and undergo senescence. Thus, there is a great need in the art for platforms allowing for generation of materials relevant to mammary development and breast cancer formation.
Described herein are induced pluripotent stem cell (“iPSC”) related reprogramming techniques allowing for production of mammary-derived iPSCs (“m-iPSCs”). Importantly, the m-iPSCs described herein exhibit all the hallmarks of stem cell identity including round cluster, bright colony morphology, clonal expansion, and pluripotent marker expression (alkaline phosphatase expression, Oct-4, nanog, etc.) Further refined techniques allow for generation of m-iPSCs under essentially defined conditions.